It is estimated that over 170 million people are infected by hepatitis C virus (HCV) worldwide. Currently, there are limited therapeutic agents and no vaccine available for HCV infection. Thus, it is necessary to develop new anti-HCV drugs. HCV is a member of the family Flaviviridae. The HCV genome contains a long, single open reading frame mRNA that encodes the viral proteins. An internal ribosome entry site (IRES) cis-acting element was identified in the 5' untranslated region of the HCV RNA, which directs translation initiation of the viral proteins. The HCV IRES has conserved primary sequences, unique secondary and tertiary structures, and a distinct interaction mode with cellular initiation factors. Based on our expertise in drug discovery, i.e. targeting Post-Transcription-Control, we are pursuing HCV IRES-mediated translation initiation against HCV infection. Using HCV IRES translation assays established at PTC, we have identified low molecular weight lead compounds that are selective against HCV IRES-mediated translation. The goal of the application is to perform lead optimization for improving the activity, selectivity, cytotoxicity and pharmacological properties of these compounds. A successful outcome of the proposed studies will be the identification of a development candidate(s) that acts on HCV IRES-facilitated translation initiation.